Low O 2 -induced ATP release from erythrocytes of humans with type 2 diabetes is restored by physiological ratios of C-peptide and insulin

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2014-10, Vol.307 (7), p.R862-R868
• Main Authors: Richards, Jennifer P., Yosten, Gina L. C., Kolar, Grant R., Jones, Cory W., Stephenson, Alan H., Ellsworth, Mary L., Sprague, Randy S.
• Format: Article
• Language: English
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00206.2014

ATP release from erythrocytes in response to reduced oxygen (O 2 ) tension stimulates local vasodilation, enabling these cells to direct perfusion to areas in skeletal muscle in need of O 2 . Erythrocytes of humans with type 2 diabetes do not release ATP in response to low O 2 . Both C-peptide and insulin individually inhibit low O 2 -induced ATP release from healthy human erythrocytes, yet when coadministered at physiological concentrations and ratios, no inhibition is seen. Here, we determined: that 1) erythrocytes of healthy humans and humans with type 2 diabetes possess a C-peptide receptor (GPR146), 2) the combination of C-peptide and insulin at physiological ratios rescues low O 2 -induced ATP release from erythrocytes of humans with type 2 diabetes, 3) residual C-peptide levels reported in humans with type 2 diabetes are not adequate to rescue low O 2 -induced ATP release in the presence of 1 nM insulin, and 4) the effects of C-peptide and insulin are neither altered by increased glucose levels nor explained by changes in erythrocyte deformability. These results suggest that the addition of C-peptide to the treatment regimen for type 2 diabetes could have beneficial effects on tissue oxygenation, which would help to ameliorate the concomitant peripheral vascular disease.